Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Researchers Uncover Secrets of Immune System’s Munitions Factory


Howard Hughes Medical Institute researchers have discovered a new component of the machinery immune cells use to generate a remarkably diverse array of antibodies from a relatively small number of genes.

The discovery reveals important links in the molecular pathway by which complex genetic alterations arm the immune system to target myriad potential bacterial and viral invaders with swiftness and precision. The discovery may also provide welcome new information about lymphoma, a form of leukemia in which certain cells of the immune system proliferate uncontrollably.

“While this is currently pure speculation, it might be that deregulation of AID activity could lead to mutations that could be involved in the evolution of lymphoma.” Frederick W. Alt

Howard Hughes Medical Institute investigator Frederick W. Alt led the research team that published its findings August 26, 2004, in the journal Nature. Alt and lead author Jayanta Chaudhuri are at Children’s Hospital, Boston, and Harvard Medical School.

The studies focus on B cells, specialized immune cells responsible for producing antibodies, and how an enzyme in those cells known as activation-induced cytidine deaminase (AID) triggers mutations of antibody gene segments to produce an assortment of antibody proteins. This process enables the immune system to produce antibodies that will recognize billions of different antigens - the fragments of foreign invaders that are used to call the immune system to arms.

The presence of an antigen on the surface of a B cell stimulates it to produce antibodies. An important step in this process is the activation of AID, which causes largely random mutations in the genes for the antibody segments that recognize antigens. These mutations occur about a million times more frequently than spontaneous mutations in other genes. In this process, known as somatic hypermutation, AID selectively “damages” the DNA strand, prompting the DNA repair system to create the mutations.

AID also triggers class switch recombination, a highly specific process that involves recombining gene segments that encode the part of the antibody molecule that direct it where to take its antigen cargo and how to dispose of it.

A central mystery in the field of immunology, said Alt, has been how AID acts on antibody genes. In previous studies, Alt and his colleagues showed that the enzyme acts on single-stranded DNA and that, for class switch recombination, such single-stranded DNA can be unraveled from native double-stranded DNA during the process of copying its information to RNA, the cell’s template for production of antibody proteins. However, this mechanism could not explain how AID works during somatic hypermutation.

In the current work, Chaudhuri developed techniques to isolate purified AID from B cells and test its activity on the target for somatic hypermutation. In this way, he found that the enzyme requires an unknown co-factor that was critical for AID function and that this co-factor specifically interacts with AID.

Subsequent analysis revealed that Chaudhuri’s protein was replication protein A (RPA), long known to be part of the DNA replication and repair machinery that attaches to single-stranded DNA.

“RPA was never even suspected to be a candidate for such a role, since it was never suspected that it could get into DNA during RNA transcription,” said Alt. “Until now, it was only known to be involved in certain DNA replication and repair pathways.” Chaudhuri also found that after AID “damages” the DNA, it leaves the complex, but RPA remains. “We believe that RPA is sitting there on the DNA, and it’s recruiting DNA repair factors, which is a great link to the repair machinery needed for the next step in the hypermutation pathway,” said Alt. Thus, in retrospect, RPA’s involvement makes biological sense.

The other major discovery, said Alt, was that for AID to interact with RPA, AID must undergo some modification in B cells - a clue to the nature of the machinery that initiates somatic hypermutation, and a topic for future studies in Alt’s lab.

Identifying RPA’s involvement could have implications for understanding lymphomas. “Lymphomas and some mature B cell tumors are known to show aberrant somatic hypermutation and class switching,” said Alt. “Now that we know more about how the AID-RPA complex works, we can begin to address questions of how the aberrant processes might occur.

“While this is currently pure speculation, it might be that deregulation of AID activity could lead to mutations that could be involved in the evolution of lymphoma,” Alt said. “Also, there might be a mutation in AID or its co-factors that would deregulate it and cause it to target other genes,” he said.

Additional studies will seek to connect the AID-RPA complex with the cell’s repair mechanism to further elucidate the somatic hypermutation and class switch recombination processes, said Alt. “We’d like to figure out how those downstream steps in these two different situations lead in one case to mutation and in the other case to recombination,” he said. “Now that we know more about how AID links to the next steps through RPA, we can begin to address this problem, which is a major question in the field.”

Jim Keeley | EurekAlert!
Further information:

More articles from Life Sciences:

nachricht Strong, steady forces at work during cell division
20.10.2016 | University of Massachusetts at Amherst

nachricht Disturbance wanted
20.10.2016 | Max Delbrück Center for Molecular Medicine in the Helmholtz Association

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

Im Focus: New Products - Highlights of COMPAMED 2016

COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.

In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...

Im Focus: Ultra-thin ferroelectric material for next-generation electronics

'Ferroelectric' materials can switch between different states of electrical polarization in response to an external electric field. This flexibility means they show promise for many applications, for example in electronic devices and computer memory. Current ferroelectric materials are highly valued for their thermal and chemical stability and rapid electro-mechanical responses, but creating a material that is scalable down to the tiny sizes needed for technologies like silicon-based semiconductors (Si-based CMOS) has proven challenging.

Now, Hiroshi Funakubo and co-workers at the Tokyo Institute of Technology, in collaboration with researchers across Japan, have conducted experiments to...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

Innovative technique for shaping light could solve bandwidth crunch

20.10.2016 | Physics and Astronomy

Finding the lightest superdeformed triaxial atomic nucleus

20.10.2016 | Physics and Astronomy

NASA's MAVEN mission observes ups and downs of water escape from Mars

20.10.2016 | Physics and Astronomy

More VideoLinks >>>